This proposal is a competitive renewal application in which in the previous cycle we demonstrated that both protein kinase C epsilon (PKC?) and resveratrol emulated ischemic preconditioning (IPC) in brain and that IPC, PKC? and resveratrol upregulate BDNF levels, which played a key role in neuroprotection. We also demonstrated that IPC and resveratrol preconditioning (RPC) induced neuroprotection via SIRT1 activation. SIRT1 activates hypoxia inducible factor-2 alpha (HIF-2?) 1 and Akt 2, transcription factors involved in other preconditioning pathways 3,4,5 and is also known to play a role in epigenetics. Epigenetic changes have been suggested to play a key role in preconditioning 6,7. We now present evidence that RPC neuroprotection lasts at least 14 days and that SIRT1 brain levels are elevated during that time. Resveratrol has previously been shown to be neuroprotective against cerebral ischemia activating many pathways that protect mitochondria 8 and promote angiogenesis 9 to name a few. The main goals of the new funding cycle are to define the specific molecular targets of IPC that promote ischemic tolerance and to further define the molecular mechanisms of a chronic ischemic tolerant state. The specific aims are 1) to define the maximum window of neuroprotection against cerebral ischemia afforded by resveratrol preconditioning (RPC); 2) to define whether this extended window of neuroprotection by RPC against cerebral ischemia is SIRT1 dependent; 3) to determine mechanisms by which RPC promotes ischemic tolerance in the delayed window; and 4) to define the molecular underpinnings of the long-term neuroprotection conveyed by RPC.